(1) Field of the Invention
The present invention relates to a non-fiber composition prepared from an organic extract of psyllium which is anti-tumorigenic. The composition both restores gap junctional intercellular communication (GJIC) and inhibits anchorage independent growth of mammalian cells which have been transformed with the ras oncogene. The composition is a useful chemotherapy and chemopreventative agent. The composition was identified using a novel method for determining the anti-tumorigenic potential of a compound or composition.
(2) Description of Related Art
Psyllium is a common source of soluble fiber derived from the husk of the plant Plantago ovata. Although the epidemiological evidence is not entirely consistent, dietary fiber has been linked to the prevention of cancers, particularly of the colon and breast (Greenwald et al., Eur. J. Cancer 37: 948–965 (2001); Gerber, J. Natl. Cancer Inst. 88: 857–858 (1996); Terry et al., J. Natl. Cancer Inst. 93: 525–533 (2001)). The underlying mechanisms by which dietary fiber can contribute to cancer prevention are not known. Among some of the potential mechanisms proposed for psyllium are the presence of the anticarcinogenic phytates, isoflavonoids, and protease inhibitors in psyllium fiber, and decreases in the circulation of tumor-promoting estrogens either through suppression of bacterial B-D-glucuronidase activity in the colon and cecum or direct binding of estrogens to fiber (Cohen et al., J. Natl. Cancer Inst. 88: 899–907 (1996)).
Neither the stage nor stages of the multi-step/multi-mechanism nature of the carcinogenic process is known as to where the anticarcinogenic properties of psyllium are effective. Although the effect of psyllium was most pronounced in reducing mammary adenocarcinoma, psyllium also decreased ductal carcinomas (Cohen et al., J. Natl. Cancer Inst. 88: 899–907 (1996)). Since ductal carcinomas are a morphologic continuum from an original initiating event to a fully developed carcinoma (Boone et al., Cancer Res. 52: 1651–1659 (1992)), then the clonal expansion stage of cancer development might be a target of psyllium.
One hypothesis of the tumor promotion mechanism is that the clonal expansion of an initiated cell results from a series of epigenetic events that remove this initiated cell from growth suppression via the inhibition of gap junctional intercellular communication (GJIC) and that activate mitogenic signal transduction pathways (Upham and Wagner, Toxicol. Sci. 64: 1–3 (2001); Trosko and Ruch, Front. Biosci. 3: 208–236 (1998); Rummel et al., Toxicol. Sci. 49: 232–240 (1999)). Gap junctions are channels between contiguous cells allowing the passive transfer of low molecular weight molecules, and are made up of protein subunits termed connexins (Goodenough, Annu. Rev. Biochem. 65: 475–502 (1996); Kumar and Gilula, Cell 84: 381–388 (1996)). Connexin genes have been shown to function as tumor suppressor genes (Trosko and Ruch, Front. Biosci. 3: 208–236 (1998); Yamasaki et al., Novartis. Found. Symp. 219: 241–254 (1999)). Transfection of connexin genes into neoplastic cells results in the restoration of GJIC and reversal of the transformed phenotype (de-Feijter-Rupp et al., Carcinog. 19: 747–754 (1998); Huang et al., Cancer Res. 58: 5089–5096 (1998); Hirschi et al., Cell Growth Differ. 7: 861–870 (1996); Rose et al., Carcinog. 14: 1073–1075 (1993); Mesnil et al., Cancer Res. 55: 629–639 (1995); Naus et al., Cancer Res. 52: 4208–4213 (1992)). Similarly, some anticarcinogenic compounds, such as retinoids (Mehta et al., J. Cell Biol. 108: 1053–1065 (1989); Mehta and Loewenstein, J. Cell Biol. 113: 371–379 (1991); Mehta et al., Cell 44: 187–196 (1986); Hossain et al., Carcinog. 10: 1743–1748 (1989)), carotenoids (Zhang et al., Carcinogenesis 12: 2109–2114 (1991)), caffeic acid (Na et al., Cancer Letts. 157: 31–38 (2000)) and lovastatin (Ruch et al., Mol. Carcinog. 7: 50–59 (1993)), are also known to upregulate GJIC, either by preventing the inhibition of GJIC by tumor promoters or by the restoration of GJIC in tumor cells with expressed but non-functional connexins in neoplastic cell lines that result in reversing the transformed phenotype. Green tea extract, which inhibits promotion of tumors in livers (Klaunig, Prev. Med. 21: 510–519 (1992)), also prevents the in vivo inhibition of GJIC in the liver tissues of rats treated with the tumor promoter, pentachlorophenol (Sai et al., Carcinog. 21: 1671–1676 (2000)). Published U.S. patent application Ser. No. 2001/0024664 A1 to Obukowicz et al. discloses that organic extracts prepared from edible plant materials, including psyllium, contain COX-2 inhibitory compounds which are useful for relieving pain, including pain produced by cancers. There is no suggestion that the organic extracts be used to treat cancers per se.
Notwithstanding the forty-year war on cancer and the deliberate progress which has been made toward improving the prognosis for many types of cancer, cancer remains a killer that continues to terrorize the population. With the recent discoveries of natural plant compounds that have anti-cancer properties, the idea that there might be plant products which will provide even more efficacious anti-cancer compounds has captured the imagination of medical research teams around the world. Therefore, there remains a need for compounds and compositions isolated from natural sources which have anti-cancer and anti-tumor properties.